This invention relates to a novel mechanism of neuropsychiatric intervention. More particularly, this invention is directed to pharmaceutical formulations and methods for treatment of a variety of neurological disease states, including cognitive and behavioral disorders.
The pharmaceutical industry has directed extensive research and development efforts toward discovery and commercialization of drugs for treatment of neurological disorders. Such disorders typically derive from chemical imbalances in the brain. Overproduction or underproduction of pertinent neurochemical species and/or receptor dysfunction has been identified with many disease states recognized by neurologists, psychiatrists, psychologists and other medical practitioners skilled in the diagnosis and treatment of mental disease. Most of the discovery effort for new neurologically active drugs has been based on the study of agonist/antagonist drug interaction with one or more of the numerous receptors in the brain and/or their respective receptor ligands.
The present invention provides a novel approach to drug intervention in the treatment of a wide variety of neurologic disease states and other disease states or clinical conditions of related etiology. It is based in part on the discovery that xcex2-lactam containing compounds known for their activity as inhibitors of bacterial peptidases or proteases, particularly transpeptidases and/or carboxypeptidases, are also potent inhibitors of certain mammalian neuro-peptidases, including N-acetylated-xcex1-linked acidic pediptidases (NAALADases), several of which have been identified/characterized in the literature [Pangalos et al., J. Biol. Chem., 1999, 274, No. 13, 8470-8783]. The present invention is also based in part on the discovery that neurogenic carboxypeptidases can be targeted with carboxypeptidase inhibitors to effect significant behavioral modification and enhanced cognitive performance. Preliminary studies have confirmed that one or more neurogenic proteases, now believed to be NAALADases and related peptidases and transferases, capable of recognizing and transforming certain neuropeptides (e.g., N-acetyl-L-aspartyl-L-glutamate) play a significant if not dominant role at the neurochemical level of brain function and concomitantly have a substantial impact on patient behavior and cognitive performance. It has been previously reported that certain glutamate analogs acting as NAALADase inhibitors can be used to treat prostate disease and glutamate abnormalities associated with certain nervous tissue insult. It has now been determined that certain xcex2-lactam-containing bacterial peptidase inhibitors capable of blood-brain barrier transport, can function in the brain at very low concentrations as potent neuroactive drug substances to reduce the symptoms of a wide variety of neurological disorders characterized by behavioral aberration or sensory/cognitive dysfunction. Significantly, such bacterial enzyme inhibitors are believed to be effective inhibitors of neurogenic peptidases, particularly carboxypeptidase E, at concentrations below those concentrations known to be required for clinically effective bacterial enzyme inhibition.
Accordingly, one embodiment of the present invention is directed to a method for treatment of cognitive and behavioral disorders in warm-blooded vertebrates by administering compounds known for their activity as bacterial protease or peptidase inhibitors, which compounds, when present at effective concentrations in the brain, have now been determined to be capable of inhibiting or otherwise modulating the activity of one or more neurogenic enzymes.
In a related embodiment there is provided method for treatment of cognitive and behavioral disorders in a patient in need of such treatment. The method comprises the step of inhibiting neurogenic peptidases, particularly, carboxypeptidase E and related neurogenic enzymes. Such neuropeptidase inhibition is effected by administering an effective amount of a xcex2-lactam compound recognized for its capacity to bind to and inhibit a bacterial enzyme, for example, a xcex2-lactamase or a bacterial protease involved in bacterial cell wall synthesis. Such bacterial proteases are known in the art as xe2x80x9cpenicillin binding proteins.xe2x80x9d xcex2-lactam compounds for use in this invention are moxalactam, its salts, esters and structrually related cephems and 1-oxa-1-dethia cephems. Effective inhibition of such neuro-carboxypeptidase E and related neuro-peptidase activity in warm-blooded vertebrates in accordance with this invention has been found to produce marked enhancement in cognitive performance and behavioral management.
Exemplary of cognitive and behavioral disorders susceptible to treatment in accordance with this invention include aggressive disorder, obsessive compulsive disorder, anxiety, depression, ADHD, and memory impairment. Animal data suggest that the method and formulation of this invention have potential as an antiaggressive agent to control impulsivity and violence in autism, Tourette""s syndrome, mental retardation, psychosis, mania, senile dementia and individuals with personality disorders and history of inappropriate aggression. Clinic applications extend to the treatment of children with ADHD and conduct disorder, as an anxiolytic, and as a cognition enhancer for the geriatric population to improve learning and memory and to ameliorate disorientation.
In another embodiment of this invention there is provided a method of treating a patient afflicted with a condition, or disposed to development of a condition, characterized at least in part by abnormal extracellular concentration of glutamate in the brain or other nervous tissue. The method comprises the step of administering to the patient in effective amounts of a compound capable of inhibiting the activity of a penicillin-binding protein of bacterial origin. The composition is administered in an amount effective to prevent or alleviate the symptoms of such condition. The method and formulation embodiments of the invention find use in both human health and veterinary applications, e.g., in canine, feline and equine species.
In one embodiment of the present invention a warm-blooded vertebrate, most typically a human patient, affected by a neurologic disease state characterized by cognitive or behavioral abnormalities is treated with a 1-oxa-1-dethia cephalosporin, more preferably a 7-methoxy-1-oxa-1-dethia cephalosporin, optionally as an active ester derivative in an orally (including buccal or sublingual administration) or a parenterally administered formulation. In one embodiment, the peptidase inhibitor is moxalactam, [7-xcex2-[2-carboxy-2-(4-hydroxyphenyl)acetamido]-7xcex1-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-1-oxa-1-dethia-3-cephem-4-carboxylic acid], described and claimed with related compounds, including their orally absorbed active ester derivatives, in U.S. Pat. No. 4,323,567, the specification of which is expressly incorporated herein by reference. Moxalactam has been found to exhibit significant dose responsive neuroactivity when administered parenterally at least at about 50 xcexcg/kg of body weight.
In another embodiment of the present invention there is provided a pharmaceutical formulation for treatment with consequent reduction of symptoms of behavioral or cognitive disorders in patients in need of such treatment. The formulation comprises a compound characterized not only by its affinity to bacteria derived penicillin-binding proteins, but as well, its affinity to neurogenic carboxypeptidases, particularly carboxypeptidase E. In that embodiment the level of activity exhibited by the carboxypeptidase inhibitor in the present method is not only dependent on its affinity to penicillin-binding proteins and to carboxypeptidase, namely carboxypeptidase-E, it is also particularly dependent on ability of the inhibitor compound to cross the blood brain barrier to achieve levels in the brain effective to modify patient behavior and/or cognitive performance. While the formulations of this invention can be prepared specifically for any art-recognized mode of administration capable of achieving threshold minimum protease inhibiting concentrations in the brain, they are typically formulated for parenteral or oral administration, optionally in the form of prolonged release or xe2x80x9cdrug depotxe2x80x9d type formulations well known in the art.